Previous studies have demonstrated that the increased fragility of aged bone correlates significantly with the integrity of collagen in bone. However, the underlying mechanism is poorly understood. The objective of this study is to elucidate how age-related changes are induced in the collagen network and whether such changes lead to the deterioration in bone quality. In this proposed study, we attempt to investigate the age-related effect of bone remodeling on the integrity of collagen and its correlation with the reduced toughness of the tissue. It has been known that newly formed secondary osteons are formed through bone remodeling process. Thus, by studying changes in the secondary osteons, one can examine the age-dependent effect of bone remodeling on the collagen integrity and the quality of bone. Our hypothesis of the present proposal is that age-dependent changes in collagen molecules are induced through bone remodeling process; and such changes directly contribute to the decreased toughness of aged bone. To this end, the following Specific Aims will be addressed: Aim 1. To examine age-related changes in material properties of the secondary osteons- Hypothesis: Material properties of secondary osteons change with increasing age. Three-point bending test specimens will be prepared from the secondary osteons and interstitial bone regions of sixty human cadaveric femurs using a micromachining device. The specimens will be tested in a micro mechanical testing device. The age-related effect of bone remodeling on the mechanical integrity of secondary osteons and interstitial bone tissues will be investigated. Aim 2. To examine age-related changes in collagen molecules within the secondary osteons-Hvpothesis: The integrity of collagen molecules in secondary osteons changes with age. The specimens mechanically tested in Aim 1 will be reused to determine the collagen integrity in the secondary osteons and interstitial bone regions. Collagen denaturation and crosslinks concentrations will be determined using high performance liquid chromatography techniques. Then, the age-related effect of bone remodeling on the integrity of collagen in bone will be investigated. In addition, the correlation of collagen integrity and mechanical behavior of secondary osteons will be explored. Aim 3. To explore the correlation of age-related changes in collagen with the decreased toughness of bone-Hypothesis: Age-related changes in collagen directly contribute to the decreased toughness of aged bone. Bulk mechanical properties of the collagen network and bone will be determined as a function of age in conjunction with other compositional and structural properties. Combining the results of Aims 1 and 2, the role of collagen in the age-related decrease in bone toughness will be investigated. This study will provide insights in the underlying mechanism of age-related deterioration in bone quality and will facilitate future studies in the prevention and treatment of age and disease-related bone fractures. [unreadable] [unreadable]